Pharmacological Properties

Limitations of Currently Available Antipsychotic Medications

The introduction of newer ► second-generation antipsy-chotics (SGAs) represents an important advance in the pharmacologic treatment of schizophrenia since the advent of ► chlorpromazine, the prototypical ► firstgeneration antipsychotics (FGAs). However, current evidence suggests that the clinical benefits of SGAs in terms of efficacy are modest at best (Leucht et al. 2009), and the effect sizes on ► cognitive impairment are small. In the largest and longest effectiveness trial, the ► clinical anti-psychotic trials of intervention effectiveness (► CATIE) study, no substantial advantage for the SGAs was demonstrated over the FGA for the treatment of negative and cognitive symptoms (Lieberman et al. 2005). Negative and cognitive symptom domains are recognized as a core feature of schizophrenia and play a greater role in poor functional outcome. Thus, it is obvious that there is a distinct need to identify and validate novel molecules that possess pharmacological profiles that better treat these symptom domains.

To date, the prototypical SGA ► clozapine remains the "gold standard'' antipsychotic drug because of a lower liability for ► extrapyramidal motor side effects (EPS) and because it has proved superior to all other ► antipsy-chotic drugs in efficacy (Leucht et al. 2009), particularly in treatment-resistant schizophrenia. However, even with clozapine, a significant number of patients are unresponsive to treatment and it carries a risk of serious side effects such as agranulocytosis, weight gain, and metabolic abnormalities. Because individuals with schizophrenia have many risk factors that may predispose them to poor health and excess mortality, safety and tolerability of antipsychotic medications are an essential treatment concern. Furthermore, remission and recovery rates for schizophrenia by the treatment with current antipsychotic medications are discouragingly low. Thus, it is important to pursue the development of more tolerable and more effective antipsychotics than clozapine. To expedite the clinical development of such drugs, biological or surrogate markers of the illness and treatment effects using chemical technologies (e.g., ► PET imaging) must be identified and validated to enable more efficient and reliable proof of efficacy of novel compounds.

Challenges of Future Drug Discovery

A number of mechanisms of action of antipsychotics have been explored during the past 30 years. However, it is still unclear as to what pharmacological profile of antipsychotic medication is necessary to show the highest efficacy and effectiveness without serious adverse effects in the treatment of schizophrenia and other psychosis. Moreover, there is still an ongoing debate as to whether drugs selective for single molecular target (i.e., "magic bullets'') or drugs selectively nonselective for several molecular targets (i.e., "magic shotguns'') will lead to new and more effective medications for psychosis (Agid et al. 2008; Roth et al. 2004).

All currently available antipsychotic medications target dopamine D2 receptors, but one example of new multitarget strategies is the utility of combined dopamine D2-like receptor antagonism and ► serotonin 5-HT1A receptor agonism (Jones and McCreary 2008). It is suggested that the balance between D2 antagonism and 5-HT1A agonism may be critical in determining the efficacy of these compounds. In addition, further serotoner-gic strategies may be a key area of schizophrenia research such that combined activity at the D2 receptor with

► selective serotonin reuptake inhibitor, and the use of 5-HT2C receptor agonists, 5-HT6 receptor antagonists, or 5-HT7 receptor agonists may be of great interest in expanding treatment options (Jones and McCreary 2008).

Recent antipsychotic research has examined agents that have no direct effect on the dopamine system, although most of them have indirect effects on dopaminer-gic pathways. For example, with the emerging evidence for glutamatergic dysregulation in schizophrenia, a number of agents with direct or indirect activity on the

► glutamate system are being investigated, especially for their potential impact on cognitive and negative symptom domains (Miyamoto et al. 2005). Glutamate-based agents in various stages of development include agonists at the glycine allosteric site of the ► N-methyl-D-aspartate (NMDA) receptor, ► glycine transporter 1 inhibitors,

► Group II metabotropic glutamate receptor agonists, a-amino-3-hydroxy-5-methy-isoxazole-4-propionic acid (AMPA)/kainate receptor antagonists, and higher-potency

► ampakines. The putative antipsychotic action of these drugs has been studied as monotherapy and/or add-on treatment (Gray and Roth 2007).

It has also been suggested that the central cholinergic system is involved in the cognitive deficits observed in schizophrenia, and enhanced cholinergic activity may improve these deficits (Miyamoto et al. 2005). Currently available treatments which are potentially suitable for this purpose include ► acetylcholinesterase inhibitors (e.g., galantamine), partial ► muscarinic agonists (e.g., xano-meline), ► nicotinic agonists, and allosteric potentiators of nicotinic receptor function (Gray and Roth 2007). These potential ► cognitive enhancers may be better suited to particular stages of schizophrenia, perhaps showing efficacy in early or later stages.

In recent years, significant progress has been made on elucidating various susceptibility genes in schizophrenia, including ► dysbindin, neuregulin 1, catechol-O-methyltransferase (COMT), disrupted in schizophrenia 1 (DISC1), and others (Gray and Roth 2007). Many of these genes appear to be associated with the control of ► synaptic plasticity and glutamate transmission, especially NMDA receptor function. Research on these molecules will allow for rational drug development in which drugs are developed on the basis of targets derived from theories of pathogenesis of the disease. However, the conundrum of single-target versus multitarget agents will remain at the forefront of drug development until the etiology of the illness is fully elucidated. In the near future, optimal treatment will probably include different therapeutic agents, each uniquely targeting a specific dimension of schizophrenia (Agid et al. 2008). In other words, single-target agents will augment multitarget agents, and there is a possibility that novel biological agents will also be investigated (Nikam and Awasthi 2008).

Recently, a growing body of evidence has demonstrated that some SGAs may increase or preserve neu-rotrophic factor levels, ► neurogenesis, neuronal plasticity, mitochondrial biogenesis, cell energetic, and antioxidant defense enzymes (Lieberman et al. 2008). Moreover, specific SGAs can ameliorate the loss of gray matter in schizophrenic patients in the early stages. These neuroprotective properties of some SGAs have become more relevant in the light of the increasing acceptance by the field of a progressive pathophysiological process and possibly neurodegenerative process coincident with the onset of schizophrenia that may underlie the clinical deterioration. Ongoing research on the neu-roprotective effects of antipsychotics may reflect another mechanism of action that antipsychotics can act through that is clinically relevant and should stimulate the search for new agents for psychosis with novel mechanisms beyond the monoaminergic systems (Lieberman et al. 2008).

New Preparations of Antipsychotic Medications

At present, antipsychotic medications are available as tablets, liquid concentrates, orally dissolving formulations, short-acting intramuscular (I.M.) preparations, or long-acting injection (LAI) preparations. Among them, several SGA LAI preparations have been and are being developed. By increasing the available treatment choices for clinicians and patients alike, new preparations such as drug-in adhesive transdermal patches and nasal spray are a welcome development. Researchers must study these preparations beyond the usual registration package.

Moving Toward the Future Individualized Treatment

There is a great need for the development of novel methods to identify optimum individualized treatment plans. In particular, the efficacy and tolerability of anti-psychotics could be directly influenced by genetic variations in ► cytochrome P450 (CYP) enzymes. Their activity may also be influenced by genetic alterations affecting the drug target molecule, such as monoaminergic receptors, neurotransmitter transporters, and enzymes. In the future, genetic tests for the pretreatment prediction of drug metabolic status, antipsychotic response, and drug-induced side effects such as EPS and weight gain are expected to bring enormous clinical benefits by helping to chose the medication, adjust therapeutic doses, and reduce adverse reactions (Arranz and de Leon 2007). Further development of genetic tests and ► pharmacogenetic research into genetically determined drug metabolic polymorphisms as well as ► pharmacogenomic strategies to the identification of novel factors influencing response would lead to a better understanding of the rational basis for the personalization of antipsychotic treatment. In addition, antipsychotic drugs may also be targeted to specific patient subgroups based on profiling and the identification of endophenotypes of schizophrenia. Clinical implementation of this practice may have a strong impact in reducing adverse effects and improving treatment adherence and efficacy (Arranz and de Leon 2007).

Conclusion

Future drug discovery approaches will have to be truly revolutionary, but there is a hope that we could obtain novel antipsychotic drugs with greater efficacy and improved safety profiles. These drugs, however, alone may not produce a complete cure. It is essential that all of the pharmacologic tools should always be used in combination with psychosocial and psychotherapeutic intervention to optimize overall ► quality of life and return patients to the best level of functioning.

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